摘要Piezo1 channels play important roles in physiological processes such as tactile sensation,blood pressure(BP)control,cardiac development,inflammatory responses as well as in disease processes.Sarco-endoplasmic reticulum Ca2+-transporting ATPase(SERCA)is the only active protein in the SR that orchestrates calcium homeostasis by translocation of Ca2+from the cytoplasm to the sarcoplasmic reticulum.It has been shown that SERCA2 inhibits Piezo1 function in mammals by directly acting on the Piezo1 mechano-transduction module of mechanosensitive ion channels.In this study,we investigated whether SERCA2 regulates Piezo1 activation indirectly by modulating Ca2+homeostasis.We showed that treatment with a Piezo1 agonist Yoda1(5 μM)markedly increased the viability and ATP synthesis of primary cardiomyocytes as well as intracellular Ca2+content through activation of Piezo1,and upregulated the expression of Piezo1 and SERCA2 in the cardiomyocytes.However,si-Piezo1 transfection resulted in downregulation of SERCA2 expression with opposite effects on viability and ATP synthesis and intracellular Ca2+content that could not be reversed by application of Yoda1.Interestingly,application of a SERCA2 channel inhibitor paxilline(Pax,10 μM)reversed the inhibitory effect of si-Piezo1 transfection on cardiomyocyte function.Using patch clamping and Ca2+transient analyses in cardiomyocytes,we demonstrated that application of Pax inhibited Yoda1-mediated Ca2+currents and APD50,confirming that Piezo1 activation by Yoda1 was significantly inhibited by Pax.Furthermore,application of Yoda1 was able to reverse si-SERCA2 transfection-induced impairment of myocardial function.Microinjection of Yoda1 and Pax into nodose ganglion(NG)in HFD-HTN model rats also demonstrated that the effect of Yoda1 was inhibited in the presence of Pax,thus confirming that Pax inhibited intracellular Ca2+recycling by SERCA2.These results demonstrate for the first time that the application of Pax inhibits the recycling of intracellular Ca2+by SERCA2 and reverses the reduction in cardiomyocyte function caused by downregulation of Piezo1 expression.